Novel therapy for alcoholic liver disease-associated hepatorenal syndrome

酒精性肝病相关肝肾综合征的新疗法

基本信息

批准号：
10378282
负责人：
Shyamasundaran Kottilil
金额：
$ 98.52万
依托单位：
MITOPOWER LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-25 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378282
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Aging Alcoholic Liver Diseases Alcohols Animal Model Biogenesis Canis familiaris Cell physiology Clinical DNA Damage Development Dose Formulation Functional disorder Funding Gene Expression Goals Hemodialysis Hepatic Hepatocyte Hepatorenal Syndrome Histology Hospitalization Human Immune Immunomodulators Impairment In Vitro Inflammatory Injury to Kidney Intravenous Kidney Kidney Failure Liver Liver Cirrhosis Liver diseases Mediating Metabolism Mitochondria Nicotinamide adenine dinucleotide Organ failure Outcome Oxidative Stress Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacology and Toxicology Phase Phase I Clinical Trials Population Preparation Process Rattus Renal function Role Safety Serum Small Business Innovation Research Grant Supplementation Therapeutic Therapeutic Index Time Tissues Toxic effect Whole Blood Work acute toxicity base dihydronicotinamide first-in-human genotoxicity healthy volunteer human study improved improved outcome in vivo ischemic injury lipid biosynthesis liver injury liver transplantation mitochondrial dysfunction mortality nicotinamide-beta-riboside novel therapeutics oxidation prevent research clinical testing riboside small molecule therapeutics standard of care systemic inflammatory response tissue culture

项目摘要

Novel therapy for alcoholic liver disease-associated hepatorenal syndrome Abstract Alcoholic liver disease (ALD) results in over 400,000 hospitalizations each year in the US, with a portion of these patients developing hepatorenal syndrome with acute kidney injury (HRS-AKI). There are no current therapeutic options that specifically address the cellular dysfunction and systemic inflammatory response that leads to progressive organ failure mediated by mitochondrial dysfunction and oxidative stress by direct alcohol-mediated toxicity. This leads to impaired hepatocyte and renal function, worsening organ failure, and the need for protective renal and hepatic therapies with the goal of improving clinical outcomes for patients who develop HRS-AKI. Nicotinamide adenine dinucleotide (NAD+) is a hallmark of aging-related disease for the liver and kidney. Decreased levels and impaired synthesis of NAD+ are found in ALD accompanied by increased de novo lipogenesis and impaired mitochondrial oxidation made possible by the role of alcohol in NAD+ depletion and impaired cellular function. NAD+ supplementation with the NAD+ precursor nicotinamide riboside (NR) reverses alcohol-induced changes by increasing NAD+ levels in tissue culture, enhancing mitochondrial oxidation, mitochondrial biogenesis, and gene expression. In animal models, NAD+ supplementation with NR has been shown to improve liver histology, reduce liver injury and protect the kidneys against ischemic injury and DNA damage preventing progressive worsening of renal injury. 2,4 dihydronicotinamide riboside (NRH), , a recently identified highly potent NAD+ precursor, consistently increases intracellular NAD+ levels to a greater extent than NR in liver and kidney, is stable in serum, and in addition acts as a highly potent immune modulator to dampen the systemic inflammatory state. Given the significant depletion in NAD+ levels in both liver and kidney in patients with ALD, NRH has the potential to reverse or prevent progression of HRS-AKI in ALD patients in combination with the standard of care. In this Fast Track study, we will complete IND-enabling studies of our proprietary intravenous formulation of NRH, MP04, followed by a Phase 1 clinical trial to investigate its safety and tolerability in humans. The outcome of this work will be a novel therapeutic for ALD-associated HRS.

酒精性肝病相关肝肾综合征的新疗法抽象的在美国，酒精性肝病 (ALD) 每年导致超过 400,000 人住院，其中一部分患有肝肾综合征伴急性肾损伤（HRS-AKI）的患者。目前尚无治疗方法专门解决导致细胞功能障碍和全身炎症反应的选择由线粒体功能障碍和直接酒精介导的氧化应激介导的进行性器官衰竭毒性。这会导致肝细胞和肾功能受损，器官衰竭恶化，需要保护性药物肾脏和肝脏治疗，旨在改善 HRS-AKI 患者的临床结果。烟酰胺腺嘌呤二核苷酸 (NAD+) 是肝脏和肾脏衰老相关疾病的标志。 ALD 中发现 NAD+ 水平降低和合成受损，并伴有从头增加酒精在 NAD+ 消耗中的作用使脂肪生成和线粒体氧化受损成为可能细胞功能受损。 NAD+ 补充 NAD+ 前体烟酰胺核苷 (NR) 可逆转酒精引起的变化通过增加组织培养中的 NAD+ 水平、增强线粒体氧化、线粒体生物合成和基因表达。在动物模型中，NAD+ 与 NR 的补充已被证实研究显示可改善肝脏组织学、减少肝损伤并保护肾脏免受缺血性损伤和 DNA 损伤防止肾损伤进行性恶化的损害。 2,4 二氢烟酰胺核苷 (NRH), , 最近鉴定出高效 NAD+ 前体，持续增加细胞内 NAD+ 水平至比 NR 在肝脏和肾脏中，在血清中稳定，此外还可以作为一种高效的免疫调节剂来抑制全身炎症状态。鉴于患者肝脏和肾脏中 NAD+ 水平显着减少与 ALD 联合使用 NRH 有可能逆转或预防 ALD 患者的 HRS-AKI 进展与护理标准。在这项快速通道研究中，我们将完成我们专有的 IND 支持研究 NRH、MP04 静脉注射制剂，随后进行一期临床试验以研究其安全性和耐受性在人类中。这项工作的成果将是一种针对 ALD 相关 HRS 的新型疗法。